Abstract
Ectopic pregnancy is a potentially life-threatening condition that occurs in 0.64%–2.0% of all pregnancies. The most-common site for ectopic pregnancy is the fallopian tube. Ectopic pregnancy should be considered in the differential diagnosis for all patients with early pregnancies presenting with abdominopelvic pain or vaginal bleeding. Risk factors for ectopic pregnancy include prior history of an ectopic pregnancy, prior tubal surgery, and pelvic inflammatory disease. This diagnosis is made based on clinical history, examination, ultrasonography, and human chorionic gonadotropin (hCG) levels. Arriving at this diagnosis can be a nuanced process that often requires serial hCG levels and pelvic ultrasounds. Ectopic pregnancy can be managed medically, surgically, and, in selected patients, expectantly. Medical management utilizes methotrexate (MTX) to arrest the growth of the ectopic pregnancy, leading to eventual involution. MTX can be prescribed in single-dose, 2-dose, or multiple-dose protocols. Patients receiving MTX should be selected carefully based on absolute and relative contraindication criteria and should be counseled that a ruptured ectopic pregnancy requiring emergent surgery is still possible. Surgical treatment of ectopic pregnancy is performed preferentially via laparoscopy, and the affected fallopian tube can be excised (salpingectomy) or preserved with removal of the suspected ectopic pregnancy (salpingostomy). (J GYNECOL SURG 38:180)
Introduction
Ectopic pregnancy, or a pregnancy that implants outside the endometrial cavity, is a potentially life-threatening condition encountered by obstetrician–gynecologists.1,2 Ectopic pregnancy accounts for 0.64%–2.0% of all pregnancies, with the most-common site of implantation being the fallopian tube.1–3 Ruptured ectopic pregnancy continues to be a significant cause of pregnancy-related morbidity and mortality, accounting for 2.7% of all pregnancy-related deaths. 2 Ruptured ectopic pregnancy is also a leading cause of hemorrhage-related mortality. 2
Tubal ectopic pregnancies account for more than 90% of ectopic cases. 4 Other sites include the abdomen, cervix, interstitial portion of the fallopian tube, ovary, and cesarean scar. 4 These more-unusual types of ectopic pregnancies are associated with high morbidity and are often difficult to diagnose. 5 A heterotopic pregnancy, or an ectopic pregnancy coexisting with an intrauterine pregnancy, can also occur. Among women with naturally occurring pregnancy, the risk of heterotopic pregnancy ranges from 1 in 4000 to 1 in 30,000. 6 This risk increases significantly in women who have undergone in vitro fertilization, with the risk of heterotopic pregnancy as high as 1 in 100. 6
Important risk factors for ectopic pregnancy include prior pelvic or tubal surgery, damage to the fallopian tubes from pelvic inflammatory disease, and previous ectopic pregnancy.7,8 Women with a history of one ectopic pregnancy have an approximately 10% risk of recurrence, and this increases to >25% in a women with 2 or more prior ectopic pregnancies.6,7 Even when the prior affected fallopian tube has been removed, such a patient will still be at an increased risk of ectopic pregnancy in the remaining tube. 5 A woman with a history of infertility is also at an increased risk of ectopic pregnancy independent of how she conceives. 8 The use of assisted reproductive techniques, tubal-factor infertility, and multiple embryo transfers are also associated with an increased risk of ectopic pregnancy.9,10
While conception with an intrauterine device in place or after a tubal ligation is rare, an estimated 25%–50% of the resulting pregnancies are ectopic. 5 More-minor risk factors for ectopic pregnancy include a history of cigarette smoking and age older than 35. 8 It is also important to note that half of all women who have ectopic pregnancy do not have any known risk factors. 7
Diagnosis
Women with signs or symptoms of a ruptured ectopic pregnancy, such as a positive pregnancy test with hemodynamic instability or an acute abdomen, should be evaluated and treated in an emergent fashion. Most patients, however, present prior to rupture with nonspecific symptoms, such as first-trimester bleeding, abdominal or pelvic pain, or both. 5 Thus, a reproductive-age, sexually active woman who presents with these symptoms should be screened for pregnancy and, if the pregnancy test is positive, be considered at risk for ectopic pregnancy until a definitive diagnosis can be made.5,11,12
Asymptomatic pregnant women who have significant risk factors for ectopic pregnancy should also be evaluated for possible ectopic pregnancy. 6 Once pregnancy is verified, transvaginal ultrasound (US) evaluation should be performed, often in conjunction with quantitative serum human chorionic gonadotrophin (hCG) measurement, to confirm the diagnosis.
The findings of a gestational sac with a yolk sac, fetal pole, or both in the adnexa can definitively indicate an ectopic pregnancy.11,13,14 Other ultrasonographic findings suggestive of ectopic pregnancy include a nonhomogeneous adnexal mass separate from the ovary, or an adnexal mass with a hyperechoic ring around a gestational sac (the “ring sign”).11,15,16 However, these findings can be seen with other pelvic structures, such as a corpus luteum, paratubal cyst, hydrosalpinx, endometrioma, or bowel, and, thus, their positive predictive value is only ∼80%. 13 Visualization of a definitive intrauterine pregnancy, including a gestational sac with a yolk sac or fetal pole, virtually rules out the possibility of ectopic pregnancy with the rare exception of an heterotopic pregnancy. 14
The concept of a “discriminatory zone,” or a certain hCG value above which an intrauterine gestational sac should be visible on US, has historically been used to diagnose a nonviable gestation when a gestational sac is absent and the hCG value is above this threshold. However, the utility of the discriminatory zone has been challenged. 17 To avoid misdiagnosis and potential disruption of an intrauterine pregnancy, if the discriminatory zone is used to aid in diagnosis of a nonviable gestation, having a conservatively high hCG value of up to 3500 mIU/mL is recommended.6,17,18
Patients without definitive US findings of ectopic or intrauterine pregnancy are considered to have a “pregnancy of unknown location.” 6 For these patients who are clinically stable, serial hCG measurements (ideally obtained 2–7 days apart) can be helpful in differentiating normal from abnormal pregnancies.19,20 The minimum increase in hCG for a potentially viable intrauterine pregnancy depends on the initial hCG level, and use of minimum hCG increase as a criterion to rule out abnormal pregnancy has become more conservative.19–21
Compared to what has been stated in older literature, it is now known that normal gestations with high initial hCG values have slower increases versus gestations with lower initial hCG values.21,22 For an initial hCG level >3000 mIU/mL, the expected increase over 2 days is 33%. In contrast, the expected increase over 2 days for an initial hCG of 1500–3000 mIU/mL would be 40%, and the expected increase for an initial hCG level of <1500 mIU/mL would be 49% over the same 2 days. 21 Ninety-nine percent of normal pregnancies will have a rate of increase faster than the minimum; thus, an increase in serum hCG less than the minimum threshold is suspicious for a nonviable pregnancy.21,22
Decreasing hCG values suggest a failing pregnancy, with 95% of women with an early pregnancy loss having a decrease in hCG of 21%–35% in 2 days. 23 However, the rate of decrease in hCG also depends on the initial hCG value, with lower initial hCG values having slower decreases. 23
Even when hCG trends are consistent with an intrauterine pregnancy or early pregnancy loss, the possibility of ectopic pregnancy is still not excluded. 24 Therefore, women with decreasing hCG values should be monitored until nonpregnant levels are reached.
In clinical situations when a progressing intrauterine gestation has been reasonably excluded, uterine aspiration can be considered to help distinguish between early pregnancy loss and ectopic pregnancy. 6 If chorionic villi are identified on pathology, no further evaluation is required. If chorionic villi are absent, repeat hCG levels should be measured. A decrease of <10%–15% (an essential plateau) or an increase in hCG raises a concern for ectopic pregnancy versus incomplete uterine evacuation. In this scenario, further treatment would be required. 6
Management
Medical management
For women with suspected or confirmed ectopic pregnancy, medical management with intramuscular (IM) methotrexate (MTX) can be considered, provided there is no clinical concern for rupture. MTX is a folate-antagonist conventionally used as chemotherapy that blocks nucleic-acid synthesis by inhibiting dihydrofolate reductase. As ectopic pregnancies consist of rapidly dividing cells actively making nucleic acids, MTX acts to arrest ectopic growth, resulting in its eventual involution.6,25 Absolute contraindications to MTX administration include: hemodynamic instability; ruptured ectopic pregnancy; presence of an intrauterine pregnancy or failure to reasonably exclude an intrauterine pregnancy; breastfeeding; immunodeficiency; significant hepatic, renal, or hematologic dysfunction; active peptic ulcer or pulmonary disease; and inability to participate in follow-up.6,25
Relative contraindications to MTX are meant to connote a higher likelihood of treatment failure and include: high initial serum hCG level (>5000 mIU/mL); embryonic cardiac activity; and ectopic pregnancy size >4 cm. An increase in pretreatment hCG level of more than 50% over 2 days is associated with a higher treatment-failure rate. Refusal of blood products is another relative contraindication to MTX therapy.25–28
Patients undergoing treatment with MTX should be counseled on its potential adverse effects, which include nausea, vomiting, stomatitis, mucositis, dermatitis, vaginal spotting, abdominal pain, and allergic reactions. Less-common adverse effects include alopecia, transient transaminitis, and pneumonitis.6,29,30 Notably, the incidence of adverse effects is typically related to the dose and duration of MTX treatment. 6 Prenatal vitamins should be discontinued during MTX therapy as they may decrease the efficacy of MTX with their folic acid content. 25 Patients receiving MTX should also be counseled on the continued risk of ectopic pregnancy rupture and the importance of seeking immediate medical attention if rupture symptoms occur. 6
Multiple protocols for MTX administration have been described: single-dose; 2-dose; and a fixed multiple-dose regimen. With the single-dose regimen, IM MTX is given (50 mg/m2 of body surface area), and serum hCG levels are measured on the day of administration (day 1). hCG levels are repeated on days 4 and 7 after administration. If the hCG level decreases at least 15% between days 4 and 7, the hCG level is monitored weekly until a nonpregnant level is reached. If the hCG level decreases by <15%, there is a high risk of treatment failure. At this point, administration of an additional dose of MTX or surgical intervention should be strongly considered. 31
The 2-dose regimen follows the same hCG monitoring schedule as the single-dose protocol but includes a repeat dose of MTX on day 4 regardless of hCG level. Again, if the days 4–7 decrease in hCG level is >15%, the hCG level is monitored serially until nonpregnant levels are achieved. If the decrease is <15%, an additional dose of methotrexate should be considered. 32
The multiple-dose regimen involves administering MTX every other day alternating with folinic acid for up to 8 days. Folinic acid is used to mitigate adverse effects of more-frequent MTX dosing. hCG levels are checked on days of MTX administration, and treatment is continued until a decrease of 15% or more from the prior level is achieved. 33
Medical management of ectopic pregnancy with MTX has avoided surgical intervention successfully in 70%–95% of cases in observational studies. 34 Among the described protocols, the multiple-dose regimen was shown to be equally or more effective than the single-dose regimen. However, the multiple-dose regimen is associated with more adverse effects.34,35 The 2-dose regimen was developed in an attempt to combine the efficacy of the multiple-dose protocol, while maintaining the more-favorable side-effect profile of the single-dose protocol. 34
Studies have shown comparable success rates between single and 2-dose regimens with similar adverse-effect profiles. 35 However, the 2-dose regimen may be more successful in women with high initial hCG values. 36 Based on the existing literature, there is no consensus on the optimal MTX regimen, so choice of protocol should be based on initial hCG level and shared decision-making with the patient. 6
MTX is a potent teratogen, and the safe interval after its administration and subsequent pregnancy is ill-defined. The U.S. Food and Drug Administration–approved package insert for IM MTX recommends avoiding pregnancy for at least 1 ovulatory cycle after administration. However, MTX presence in hepatocytes has been reported as many as 116 days after use. 37 Due to this finding, a recommendation for a 3-month interval is reasonable.6,38 The current evidence suggests that MTX does not have adverse effects on ovarian reserve or subsequent fertility. 6
Surgical management
Women who are hemodynamically unstable or with signs or symptoms of a ruptured ectopic pregnancy require surgical management. Other candidates for surgical management include those for whom medical management with MTX has failed, have a contraindication to MTX, or are clinically stable but choose to undergo surgery. 6 Surgical management can be performed via laparoscopic salpingectomy (removal of the affected fallopian tube) or salpingostomy (removal of the ectopic pregnancy with tubal conservation). For hemodynamically unstable patients, laparotomy should be considered.5,6
When choosing between salpingostomy and salpingectomy, the clinical status of the patient, degree of fallopian-tube damage, and future fertility desires should all be taken into consideration. 6 While salpingostomy may have a higher rate of subsequent intrauterine pregnancy, compared to salpingectomy, in some studies, salpingostomy has also been shown to confer an increased risk of repeat ectopic pregnancy. 39 For a patient who desires future fertility and has an absent or damaged contralateral fallopian tube, salpingostomy should be considered. 6 Postoperative monitoring of serial hCG levels is needed until nonpregnant levels are reached, given that 5%–20% of women will have remaining trophoblastic tissue after salpingostomy. 5
Expectant management
For selected patients, there is a role for observation in management of ectopic pregnancy. Patients who undergo expectant management should have no symptoms indicative of ectopic rupture and should receive thorough counseling regarding the risk of rupture and subsequent need for emergent surgery. 6 Serial hCG measurements should be performed during the expectant management time and should show evidence of pregnancy resolution. Patients most likely to resolve an ectopic pregnancy spontaneously have low initial hCG values (<200 mIU/mL). 40 Contraindications to continued expectant management include suspicion for ectopic rupture (hemoperitoneum, pain, hemodynamic instability) and static or rising hCG levels.
Choosing a management plan
Providers should perform a thorough evaluation of each patient, including consideration of medical and surgical histories, reproductive desires, and clinical stability. Based on these factors and, in the absence of contraindications to a particular management modality, management decisions should hinge on mutual decision-making between patients and providers. This should be done with the understanding that future management will depend on further data collection (hCG levels, potential US results) and on the possibility of ectopic rupture.
Conclusions
Tubal ectopic pregnancy is a commonly encountered clinical problem for obstetrician–gynecologists, and appropriate diagnosis and management of ectopic pregnancy is an essential clinical skill. Reaching the diagnosis of ectopic pregnancy is often a nuanced process that is achieved with serial data collection using hCG levels and pelvic US. Once the diagnosis of ectopic pregnancy is made, there are multiple management strategies that encompass medical, surgical and expectant management. The use of these strategies should be situationally dependent and reflect consideration of clinical status and patient preference when possible.
Footnotes
Authors' Contributions
All named authors made substantial contributions to this article and are in agreement with its findings.
Author Disclosure Statement
No financial conflicts of interest exist.
Funding Information
No funding was received for this work.